Chimeric Antigen Receptor (CAR) T cell therapies have heralded a new era in oncological treatment, yielding transformative outcomes particularly in hematologic malignancies. These immunotherapies engineer patients’ own T cells to express synthetic receptors that selectively recognize and eradicate cancerous cells in the bloodstream. However, despite their spectacular success against blood cancers, CAR T cells have struggled to achieve comparable efficacy against solid tumors — a category accounting for nearly 90 percent of adult cancers worldwide. The challenges are multifaceted: solid tumors create a hostile microenvironment that hinders immune cell infiltration, demonstrate profound antigenic heterogeneity, and often employ multiple immunosuppressive mechanisms to evade destruction.
A groundbreaking study from a collaborative team at Monash University and the Peter MacCallum Cancer Centre now offers a promising avenue to surmount these obstacles by harnessing advanced gene editing technologies and targeted inhibition of intracellular immune checkpoints. Their research, recently published in the prestigious journal Science Translational Medicine, elucidates how manipulating the intracellular phosphatase PTPN2 can dramatically augment the potency and persistence of human CAR T cells engineered to target antigens prevalent in solid tumors. This approach is poised to enhance the therapeutic landscape for solid malignancies, which have lagged behind in the wake of immunotherapy triumphs.
PTPN2 (Protein Tyrosine Phosphatase Non-receptor type 2) functions as an intracellular negative regulator of T cell receptor signaling pathways. Unlike PD-1, the well-characterized cell surface checkpoint inhibitory receptor that attenuates T cell activation upon ligand binding, PTPN2 operates within the cytoplasm to fine-tune the amplitude and duration of signaling cascades pivotal to T cell activation and effector function. Given that PD-1 blockade has revolutionized cancer immunotherapy by unleashing endogenous T cell responses, targeting PTPN2 represents a complementary strategy that could potentiate or amplify these effects by modulating intracellular checkpoints.
The researchers employed cutting-edge CRISPR gene-editing to delete PTPN2 in human-derived CAR T cells effectively. Parallel pharmacological studies utilized an investigational PTPN2 inhibitor, currently in Phase 1 clinical trials for solid tumors both as a monotherapy and in combination with anti-PD-1 antibodies. This dual approach validated the potential clinical translatability of modulating PTPN2 activity. The treated CAR T cells demonstrated an enhanced cytotoxic phenotype, improved persistence, and increased production of proinflammatory cytokines—all critical parameters correlating with superior anti-tumor efficacy.
In robust murine xenograft models bearing human solid tumors, PTPN2-deficient CAR T cells induced significant tumor regression compared to untreated controls. Moreover, these genetically and pharmacologically optimized CAR T cells contributed to extended survival, showcasing durable control over tumor progression. Investigations into the underlying cellular dynamics revealed these CAR T cells adopted a stem cell–like memory phenotype, characterized by heightened self-renewal and long-term survivability. Such memory T cells can chronically surveil and eliminate residual tumor cells, which is essential for preventing recurrence and achieving sustained remission.
Professor Tony Tiganis, the study’s senior author, emphasized the translational significance of these findings. He stated that targeting PTPN2 does not merely amplify CAR T cell lethality but also fosters the generation of a durable memory T cell pool capable of infiltrating tumor microenvironments and persisting long-term. Generating and maintaining this pool is especially crucial in the context of solid tumors, where antigen heterogeneity and immunosuppressive niches typically blunt therapeutic responses. This study therefore paves the way for combinatorial immunotherapies that synergize CAR T cell engineering with checkpoint modulation at intracellular nodes.
The collaborative effort highlights a nuanced and promising avenue in cancer immunotherapy; by targeting intracellular signaling regulators such as PTPN2, it might be possible to circumvent some of the limitations imposed by tumor heterogeneity and immune evasion. However, Professor Tiganis also underscored the necessity of cautious progression towards clinical application, given the inherent risks associated with immune modulation. Because PTPN2 regulates immune signaling intensity, its inhibition may inadvertently trigger dysregulated immune responses or autoimmunity if not precisely controlled.
Dr Florian Wiede, co-lead author, provided further insights into the clinical implications. He noted the transformative impact CAR T cell therapies have had on blood cancers like leukemia and lymphoma but acknowledged that their potential against solid tumors remains an unmet need. The study’s findings offer evidence that CRISPR-mediated gene editing or small-molecule inhibitors targeting PTPN2 can reinvigorate CAR T cells, enabling them to overcome barriers intrinsic to solid cancers.
Additionally, the pharmacological PTPN2 inhibitor employed in this research represents a promising tool that could be integrated into existing immunotherapeutic regimens. Its ongoing clinical evaluation as both monotherapy and in combination with PD-1 checkpoint blockade epitomizes a rational multipronged approach to activate endogenous immunity while simultaneously enhancing adoptive cell therapy. If successful, this approach could revolutionize the current paradigm by not only extending CAR T cell efficacy to solid tumors but also by optimizing duration and potency of responses.
Mechanistically, PTPN2 acts as a brake on intracellular tyrosine kinase signaling pathways such as those mediated by the T cell receptor, thereby modulating transcription factors involved in proliferation, cytokine production, and cytotoxic functions. By genetically or pharmacologically lifting this inhibition, CAR T cells achieve a higher activation threshold and sustain effector functions for longer durations. This intracellular reprogramming fosters a phenotype akin to long-term memory T cells, which is critical for combating solid tumor heterogeneity and preventing relapse.
The significance of this work lies not only in its immediate therapeutic implications but also in the broader conceptual advance it represents in checkpoint biology. While extracellular checkpoint inhibitors such as PD-1 and CTLA-4 antagonists have garnered widespread attention, targeting intracellular immune modulators like PTPN2 broadens the scope of immune engineering. It introduces a novel layer of control that can be exploited to fine-tune immune responses with potentially greater precision and fewer systemic side effects.
In sum, this innovative approach to enhancing CAR T cell functionality via PTPN2 inhibition may herald a new frontier in solid tumor immunotherapy. By combining gene-editing techniques with emerging pharmacological agents, researchers are advancing towards more effective, durable, and safe cancer therapies. As this strategy advances through subsequent clinical stages, it could redefine therapeutic options for thousands of patients burdened by solid malignancies that currently lack curative treatments.
Subject of Research: Enhancement of human CAR T cell efficacy against solid tumors through CRISPR-mediated deletion and pharmacological inhibition of the intracellular phosphatase PTPN2.
Article Title: Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory in mouse xenograft models
News Publication Date: 4-Nov-2025
Web References: http://dx.doi.org/10.1126/scitranslmed.adk06
Keywords: Immunotherapy, Cancer immunotherapy, CAR T cells, Solid tumors, PTPN2, Gene editing, CRISPR, Immune checkpoints, T cell memory, Adoptive cell therapy
